Many hematopoietic cells express cell-surface receptors that distinguish antibody classes (e.g. IgE or IgG) through interactions with the antibody- Fc regions. The expression of these Fc receptors on many different cell types couples the diversity of the antibody response to cell-mediated immune mechanisms that include cytotoxic, degranulatory, and phagocytic reactions. Fc receptors specific for IgE and IgE and IgG fall into a common structural class with homologous extracellular immunoglobulin domains that are responsible for antibody binding. Antigen antibody complexes trigger the aggregation of Fc receptors and thereby activate cells, using signaling pathways that are analogous to those of the T and B cell receptor. Little is known about the specific structural interactions that govern the recognition of antibody classes by different Fc receptors or the subsequent signaling complexes that are formed. The goal of this proposal is to understand in atomic detail how Fc receptors discriminate between antibody molecules and to determine what role conformational changes may have in regulating binding or signaling of these receptors. In order to address these questions we have chosen to study the high affinity IgE-Fc receptor (Fcepsilon RI) from mast cells. The FcepsilonRI is important in triggering immediate-type hypersensitivities such as common allergic diseases and anaphylactic shock. The specific aims this proposal are to (1) determine the structure of the FcepsilonRI by X-ray crystallography and (2) to determine the crystallographic structures of the IgE-Fc region alone and in a complex with FcepsilonRI. We have initial crystals of the extracellular region of the Fcepsilon RI that binds antibody. In addition, Fc-fragments of the IgE molecule are being generated and will be used for further crystallization experiments. The three proposed structures will clarify at the atomic level the interaction of Fc receptor with antibody and may lead to new approaches for the treatment of allergy, arthritis, and antibody-mediated tumor immunity.